PROJECT 4: PROJECT SUMMARY Red blood cell (RBC) transfusion management includes the criteria used to determine when transfusion should occur in preterm infants. There is controversy regarding whether more restrictive or more liberal criteria would best serve the goal of optimal brain development. Although some studies have indicated that liberal transfusions may be neuroprotective, our findings from a long-term outcome study in conjunction with this PPG (2006-2010) suggested a significant sex effect with females in the liberal transfusion group having the worst neurodevelopmental outcomes. Those findings were unexpected, but led us to focus the next PPG project (2010 ? present) on short term outcomes (neonatal period). We hypothesized that transfusion-induced inflammation was a possible mechanism of poor outcome related to liberal transfusion. Our current neonatal assessment was `piggy- backed' onto the large multi-site Transfusions of Prematurity (TOP) clinical trial where preterm infants are randomized to either liberal or restricted RBC transfusion. Inflammatory cytokines were measured during the first weeks of life before and after transfusions. This was followed by an MRI brain scan at the end of the NICU stay. The overall aim was to evaluate the neurodevelopmental outcomes of differential transfusion from a mechanistic viewpoint, evaluating the role of inflammation. The preliminary data are striking and support the notion of an interaction between transfusion and inflammation with direct effects of brain structure. Moreover those changes in the brain occur in a sex specific manner. We now move into a vital timeframe in further assessment of the TOP infants. This trial presents an unprecedented and time-limited opportunity to evaluate neurodevelopmental outcomes in the context of the anemia of prematurity and its treatment (RBC transfusion). The current proposal will assess long-term neurodevelopmental outcomes of brain structure (using MRI) and brain function (using standardized tests) in children previously enrolled in TOP. Initial assessment will be done at age 5 with annual assessments at ages 6 and 7 years as change over time (developmental trajectory) is more sensitive to group differences than one cross sectional comparison. .Finally, in addition to the data from the TOP we also have cytokine data from their NICU stay, allowing assessment of the effects of early inflammation on later neurodevelopment.